PRODUCT MONOGRAPH - Sandoz Canada · Sandoz Ramipril Page 1 of 37 PRODUCT MONOGRAPH Pr SANDOZ RAMIPRIL Ramipril Tablets 1.25 mg, 2.5 mg, 5.0 mg and 10.0 mg Manufacturer's Standard

Sandoz Ramipril Page 1 of 37

PRODUCT MONOGRAPH

Pr SANDOZ RAMIPRIL

Ramipril

Tablets 1.25 mg, 2.5 mg, 5.0 mg and 10.0 mg

Manufacturer's Standard

Angiotensin Converting Enzyme Inhibitor

Sandoz Canada Inc.

145 Jules-Léger Date of Revision: June 22, 2018

Boucherville, QC, Canada

J4B 7K8

Submission Control No: 217031


Table of Contents

PART I: HEALTH PROFESSIONAL INFORMATION ........................................................................................ 3

SUMMARY PRODUCT INFORMATION .............................................................................................................. 3 INDICATIONS AND CLINICAL USE .................................................................................................................... 3 CONTRAINDICATIONS ......................................................................................................................................... 3 WARNINGS AND PRECAUTIONS ........................................................................................................................ 4 DRUG INTERACTIONS ........................................................................................................................................ 14 DOSAGE AND ADMINISTRATION .................................................................................................................... 18 OVERDOSAGE ...................................................................................................................................................... 19 ACTION AND CLINICAL PHARMACOLOGY ................................................................................................... 19 STORAGE AND STABILITY ................................................................................................................................ 21 DOSAGE FORMS, COMPOSITION AND PACKAGING .................................................................................... 22

PART II: SCIENTIFIC INFORMATION .............................................................................................................. 23

PHARMACEUTICAL INFORMATION ............................................................................................................... 23 CLINICAL TRIALS ............................................................................................................................................... 24 DETAILED PHARMACOLOGY ........................................................................................................................... 26 TOXICOLOGY ....................................................................................................................................................... 28 REFERENCES ........................................................................................................................................................ 32

PART III: CONSUMER INFORMATION ............................................................................................................. 34


Sandoz Ramipril

(Ramipril tablets)

PART I: HEALTH PROFESSIONAL INFORMATION

SUMMARY PRODUCT INFORMATION

Route of

Administration

Dosage Form/

Strength

Non-medicinal Ingredients

Oral Tablets

1.25 mg, 2.5 mg,

5.0 mg and 10.0 mg

sodium hydrogen carbonate, hypromellose,

microcrystalline cellulose, pregelatinized starch

and sodium stearyl fumarate

INDICATIONS AND CLINICAL USE

Sandoz Ramipril (ramipril) is indicated for:

Treatment of Essential Hypertension. It may be used alone or in association with thiazide

diuretics or with the calcium channel blocker felodipine.

The safety and efficacy of Sandoz Ramipril in renovascular hypertension have not been

established and therefore, its use in this condition is not recommended.

Geriatrics (>65 years of age):

Although clinical experience has not identified differences in response between the elderly (>65

years) and younger patients, greater sensitivity of some older individuals cannot be ruled out (see

ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics).

Pediatrics (< 18 years of age)

The safety and effectiveness of Sandoz Ramipril in children have not been established. Therefore,

Sandoz Ramipril is not indicated in this patient population.

CONTRAINDICATIONS

Patients who are hypersensitive to this drug, any other angiotensin converting enzyme

(ACE) inhibitor, to any ingredient in the formulation or component of the container. For a

complete listing of ingredients, see Dosage Forms, Composition and Packaging section of

the Product Monograph.

Patients who have a history of hereditary/idiopathic angioedema, or angioedema with or

without treatment with an ACE inhibitor

Pregnant and nursing women (see WARNINGS AND PRECAUTIONS, Special

Populations, Pregnant Women and Nursing Women).


Patients with hemodynamically relevant bilateral renal artery stenosis, or unilateral in the

single kidney (see WARNINGS AND PRECAUTIONS, Renal, Renal impairment).

Patients with hypotensive states or hemodynamically unstable states.

Concomitant use with sacubitril/valsartan due to an increased risk of angioedema.

Do not initiate Sandoz Ramipril until at least 36 hours have elapsed following the

last dose of sacubitril/valsartan. In the case of a switch from Sandoz Ramipril to

sacubitril/valsartan, do not start sacubitril/valsartan until at least 36 hours have

elapsed following the last dose of Sandoz Ramipril.

Combination with aliskiren-containing drugs in patients with

o diabetes mellitus (type 1 or type 2)

o moderate to severe renal impairment (GFR<60 ml/min/1.73 m2)

o hyperkalemia (> 5 mMol/L)

o congestive heart failure who are hypotensive

(see WARNINGS and PRECAUTIONS, Dual Blockade of the Renin-Angiotensin System (RAS)

and Renal, and DRUG INTERACTIONS, Dual Blockade of the Renin-Angiotensin System

(RAS).

Combination with angiotensin II receptor antagonists (ARBs) in patients with :

o Diabetes with end organ damage

o moderate to severe renal impairment (GFR<60 ml/min/1.73m2)

o hyperkalemia (> 5 mMol/L)

o congestive heart failure who are hypotensive

[see WARNINGS and PRECAUTIONS, Dual Blockade of the Renin- Angiotensin System

(RAS) and Renal, and DRUG INTERACTIONS, Dual Blockade of the Renin-Angiotensin

System (RAS)].

Combination with extracorporeal treatments leading to contact of blood with negatively

charged surfaces since such use may lead to anaphylactoid reactions. Such extracorporeal

treatments include dialysis or hemofiltration with certain high-flux (e.g. polyacrylonitril)

membranes and low-density lipoprotein apheresis with dextran sulfate (see WARNINGS

AND PRECAUTIONS, Immune).

WARNINGS AND PRECAUTIONS

General

Cough

A dry, persistent cough, which usually disappears only after withdrawal or lowering of the dose

of ramipril, has been reported. Such possibility should be considered as part of the differential

diagnosis of cough (see ADVERSE REACTIONS).

Serious Warnings and Precautions

When used in pregnancy, angiotensin converting enzyme (ACE) inhibitors can cause

injury or even death of the developing fetus. When pregnancy is detected, ramipril

should be discontinued as soon as possible (see WARNINGS AND PRECAUTIONS,

Special Populations, Pregnant Women).


Driving a vehicle or performing other hazardous tasks

Some adverse effects (e.g. some symptoms of a reduction in blood pressure (BP) such as

lightheadedness, dizziness, syncope) may impair the patient's ability to concentrate and react and,

therefore, constitute a risk in situations where these abilities are of particular importance (e.g.

operating a vehicle or machinery).

Dual blockade of the Renin-Angiotensin System (RAS)

There is evidence that co-administration of ACE inhibitors, such as ramipril, or of ARBs with

aliskiren increases the risk of hypotension, syncope, stroke, hyperkalemia and deterioration of

renal function, including renal failure, in patients with diabetes mellitus (type 1 or type 2) and/or

moderate to severe renal impairment (GFR<60 ml/min/1.73m2). Therefore, the use of ramipril in

combination with aliskiren-containing drugs is contraindicated in these patients (see

CONTRAINDICATIONS).

The use of ramipril in combination with an ARB is contraindicated in patients with diabetic

nephropathy (see CONTRAINDICATIONS).

Further, co-administration of ACE inhibitors, including ramipril, with other agents blocking the

RAS, such as ARBs or aliskiren-containing drugs, is generally not recommended in other

patients, since such treatment has been associated with an increased incidence of severe

hypotension, renal failure, and hyperkalemia (see DRUG INTERACTIONS).

Cardiovascular

Aortic Stenosis

There is concern, on theoretical grounds, that patients with aortic stenosis might be at particular

risk of decreased coronary perfusion when treated with vasodilators because they do not develop

as much afterload reduction.

Hypotension

Symptomatic hypotension has occurred after administration of ramipril, usually after the first or

second dose or when the dose was increased. It is more likely to occur in patients who are volume

depleted by diuretic therapy, dietary salt restriction, dialysis, diarrhea, vomiting, or in other

situations in which a significant activation of the RAS is to be anticipated such as in patients with

severe, and particularly malignant hypertension, in patients with hemodynamically relevant left-

ventricular outflow impediment (e.g., stenosis of the aortic valve) or in patients with

hemodynamically relevant renal artery stenosis. All patients should be cautioned about this

potential excessive fall in BP and advised to consult their physician.

Generally, it is recommended that dehydration, hypovolaemia or salt depletion be corrected

before initiating treatment (in patients with heart failure, however, such corrective action must be

carefully weighed against the risk of volume overload). When these conditions have become

clinically relevant, treatment with ramipril must only be started or continued if appropriate steps

are taken concurrently to prevent an excessive fall in BP and deterioration of renal function.

In patients with ischemic heart disease or cerebrovascular disease, an excessive fall in BP could

result in a myocardial infarction or cerebrovascular accident (see ADVERSE REACTIONS,

Clinical Trial Adverse Drug Reactions). Because of the potential fall in BP in these patients,


therapy with ramipril should be started under close medical supervision. Such patients should be

followed closely for the first weeks of treatment and whenever the dose of ramipril is increased.

In patients with severe congestive heart failure, with or without associated renal insufficiency,

ACE inhibitor therapy may cause excessive hypotension and has been associated with oliguria,

and/or progressive azotemia, and rarely, with acute renal failure and/or death.

If hypotension occurs, the patient should be placed in a supine position and, if necessary, receive

an intravenous infusion of 0.9% sodium chloride. A transient hypotensive response may not be a

contraindication to further doses which usually can be given without difficulty once the BP has

increased after volume expansion in hypertensive patients. However, lower doses of ramipril

and/or reduced concomitant diuretic therapy should be considered.

Ramipril may lower the state of patient alertness and/or reactivity; particularly at the start of

treatment (see ADVERSE REACTIONS). Patients should be cautioned to report lightheadedness,

especially during the first few days of ramipril therapy. If actual syncope occurs, the patients should

be told to discontinue the drug and consult with their physician.

Endocrine and metabolism

Hyperkalemia and Potassium-Sparing Diuretics

Elevated serum potassium (> 5.7 mEq/L) was observed in approximately 1% of hypertensive

patients in clinical trials treated with ramipril. In most cases these were isolated values which

resolved despite continued therapy. Hyperkalemia was not a cause of discontinuation of therapy

in any hypertensive patient. Risk factors for the development of hyperkalemia may include renal

insufficiency, diabetes mellitus, and the concomitant use of agents to treat hypokalemia or other

drugs associated with increases in serum potassium (see DRUG INTERACTIONS, Drug-Drug

Interactions).

Hematologic

Neutropenia/Agranulocytosis

Agranulocytosis and bone marrow depression have been caused by ACE inhibitors. Several cases

of agranulocytosis, neutropenia or leukopenia have been reported in which a causal relationship

to ramipril cannot be excluded. Current experience with the drug shows the incidence to be rare.

Hematological reactions to ACE inhibitors are more likely to occur in patients with impaired

renal function and in those with concomitant collagen disease (e.g., lupus erythematosus or

scleroderma) or in those treated with other drugs that may cause changes of the blood picture.

Periodic monitoring of white blood cell counts should be considered (see WARNINGS AND

PRECAUTIONS, Monitoring and Laboratory Tests, and ADVERSE REACTIONS, Less

Common Adverse Drug reactions, Hematologic).

Patients should be told to report promptly to their physician any indication of infection (e.g. sore

throat, fever) as this may be a sign of neutropenia (see ADVERSE REACTIONS, Post-Market

Adverse Drug Reactions).

Hepatic/Biliary


Hepatitis (hepatocellular and/or cholestatic), elevations of liver enzymes and/or serum bilirubin

have occurred during therapy with ACE inhibitors in patients with or without pre-existing liver

abnormalities. In most cases the changes were reversed on discontinuation of the drug.

Elevations of liver enzymes and/or serum bilirubin have been reported with ramipril (see

ADVERSE REACTIONS). Should the patient receiving ramipril experience any unexplained

symptoms particularly during the first weeks or months of treatment, it is recommended that a

full set of liver function tests and any other necessary investigations be carried out.

Discontinuation of ramipril should be considered when appropriate.

There are no adequate studies in patients with cirrhosis and/or liver dysfunction. In patients with

impaired liver function, response to the treatment with ramipril may be either increased or

reduced. In addition, in patients in whom severe liver cirrhosis with oedema and/or ascites is

present, the RAS may be significantly activated. Ramipril should be used with particular caution

in patients with pre-existing liver abnormalities. In such patients baseline liver function tests

should be obtained before administration of the drug and close monitoring of response and

metabolic effects should apply (see ACTION AND CLINICAL PHARMACOLOGY, Special

Populations and conditions, Hepatic Insufficiency).

Rarely, ACE inhibitors, including ramipril, have been associated with a syndrome that starts with

cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. The

mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop

jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and

receive appropriate medical follow-up.

Immune

Angioedema - Head, and Neck or Extremities

Angioedema has been reported in patients with ACE inhibitors including ramipril.

Life threatening angioedema has been reported in patients with ACE inhibitors, including

ramipril. The overall incidence is 0.1-0.2%. Angioedema involving the face, extremities, lips,

tongue, glottis and/or larynx has been reported in patients treated with ACE inhibitors.

Angioedema associated with laryngeal involvement may be fatal. If laryngeal stridor or

angioedema of the face, extremities, lips, tongue, or glottis occurs, ramipril should be

discontinued immediately, the patient treated appropriately in accordance with accepted medical

care, and carefully observed until the swelling disappears. In instances where swelling is confined

to the face and lips, the condition generally resolves without treatment, although antihistamines

may be useful in relieving symptoms. Where there is involvement of tongue, glottis, or larynx,

likely to cause airway obstruction, appropriate therapy (including, but not limited to 0.3 - 0.5 mL

of subcutaneous epinephrine solution 1:1000) should be administered promptly (see ADVERSE

REACTIONS, Clinical Trial Adverse Drug Reactions, Essential Hypertension, Less Common

Clinical Trial Adverse Drug Reactions (<1%), Body as a whole).

An increased risk of angioedema is possible with concomitant use of other drugs which may

cause angioedema.


Concomitant use of mTOR inhibitors, DPP-IV inhibitors and NEP inhibitors

Patients taking a concomitant mTOR inhibitor (e.g. sirolimus, everolimus, temsirolimus), DPP-

IV inhibitor (e.g. sitagliptin) or neutral endopeptidase (NEP) inhibitor may be at increased risk

for angioedema. Caution should be used when initiating ACE inhibitor therapy in patients already

taking a mTOR, DPP-IV or NEP inhibitor or vice versa (see DRUG INTERACTIONS).

Concomitant use of sacubitril/valsartan

A potential increased risk of angioedema has been reported with concomitant use of

sacubitril/valsartan and ACE inhibitors (see CONTRAINDICATIONS).

Angioedema — Intestinal

Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients

presented with abdominal pain (with or without nausea or vomiting); in some cases facial

angioedema also occurred. The intestinal angioedema symptoms resolved after stopping the ACE

inhibitor.

The incidence of angioedema during ACE inhibitor therapy has been reported to be higher in

black than in non-black patients.

Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased

risk of angioedema while receiving an ACE inhibitor (see CONTRAINDICATIONS).

Angioedema, including laryngeal edema, may occur especially following the 1st dose of ramipril.

Anaphylactoid Reactions During Membrane Exposure

Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes [e.g.

polyacrylonitrile (PAN)] and treated concomitantly with an ACE inhibitor. Therefore, the use of

ramipril in patients dialyzed with high-flux membranes is contraindicated (see

CONTRAINDICATIONS). Dialysis should be stopped immediately if symptoms such as nausea,

abdominal cramps, burning, angioedema, shortness of breath and severe hypotension occur.

Symptoms are not relieved by antihistamines. If such treatment is required, consideration should

be given to using a different type of dialysis membrane or a different class of antihypertensive

agents.

Anaphylactoid Reactions During LDL Apheresis

Rarely, patients receiving ACE inhibitors during low density lipoprotein apheresis with dextran

sulfate have experienced life-threatening anaphylactoid reactions. These reactions were avoided

by temporarily withholding the ACE inhibitor therapy prior to each apheresis. Therefore, the use

of ramipril in patients receiving low density lipoprotein apheresis with dextran sulfate is

contraindicated (see CONTRAINDICATIONS). If such treatment is required, consideration

should be given to using a different type of apheresis or a different class of antihypertensive

agents.

Anaphylactoid Reactions During Desensitization

There have been isolated reports of patients experiencing sustained life-threatening anaphylactoid

reactions while receiving ACE inhibitors during desensitization treatment with hymenoptera (e.g.


bees, wasps) venoma. In the same patients, these reactions have been avoided when ACE

inhibitors were temporarily withheld for ≥24 hours, but they have reappeared upon inadvertent

rechallenge.

Nitritoid Reactions – Gold

Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and symptomatic

hypotension) have been reported rarely in patients on therapy with injectable gold (sodium

aurothiomalate) and concomitant ACE inhibitor therapy including ramipril (see DRUG

INTERACTIONS).

Peri-Operative Considerations

Surgery/Anesthesia

In patients undergoing surgery or anesthesia with agents producing hypotension, ramipril may

block angiotensin II formation secondary to compensatory renin release. If hypotension occurs

and is considered to be due to this mechanism, it may be corrected by volume repletion.

Renal

Renal impairment As a consequence of inhibiting the renin-angiotensin-aldosterone system (RAAS), changes in

renal function have been seen in susceptible individuals. In patients whose renal function may

depend on the activity of the RAAS, such as patients with bilateral renal artery stenosis,

unilateral renal artery stenosis to a solitary kidney, or severe congestive heart failure, treatment

with agents that inhibit this system has been associated with oliguria, progressive azotemia, and

rarely, acute renal failure and/or death. In susceptible patients, concomitant diuretic use may

further increase risk; therefore, discontinuation of diuretic therapy may be required.

The use of ACE inhibitors – including ramipril – or ARBs with aliskiren-containing drugs is

contraindicated in patients with diabetes mellitus (type 1 or 2), moderate to severe renal

impairment (GFR<60 ml/min/1.73m2), hyperkalemia (> 5 mMol/L) or congestive heart failure

who are hypotensive (See CONTRAINDICATIONS and DRUG INTERACTIONS, Dual

Blockade of the Renin-Angiotensin-System (RAS) with ARBs, or ACE inhibitors, or aliskiren-

containing drugs).

Concomitant use of ACE inhibitors – including ramipril, with ARBs or other ACE inhibitors is

contraindicated in patients with diabetes with end organ damage, moderate to severe kidney

insufficiency (GFR < 60 mL/min/1.73m2), hyperkalemia (> 5mMol/L) or congestive heart failure

who are hypotensive (see CONTRAINDICATIONS and DRUG INTERACTIONS, Dual

Blockade of the Renin-Angiotensin-System (RAS) with ARBs, ACE inhibitors, or aliskiren-

containing drugs).

Use of ramipril should include appropriate assessment of renal function.

Ramipril should be used with caution in patients with renal insufficiency as they may require

reduced or less frequent doses (see DOSAGE AND ADMINISTRATION). Close monitoring of

renal function during therapy should be performed as deemed appropriate in patients with renal

insufficiency.


Special Populations

Pregnant Women: ACE inhibitors can cause fetal and neonatal morbidity and mortality when

administered to pregnant women. When pregnancy is detected, ramipril should be discontinued

as soon as possible, and, if appropriate, alternative therapy should be started. Patients planning

pregnancy should be changed to alternative antihypertensive treatments which have an

established safety profile for use in pregnancy.

The use of ACE inhibitors is contraindicated during pregnancy

Prematurity, and patent ductus arteriosus and other structural cardiac malformations, as well as

neurologic malformations, have been reported following exposure in the first trimester of

pregnancy.

The use of ACE inhibitors during the second and third trimesters of pregnancy has been

associated with fetal and neonatal injury including hypotension, neonatal skull hypoplasia,

anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been

reported, presumably resulting from decreased fetal renal function, associated with fetal limb

contractures, craniofacial deformation, and hypoplastic lung development.

Infants with a history of in utero exposure to ACE inhibitors should be closely observed for

hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward

support of BP and renal perfusion. Exchange transfusion or dialysis may be required as a means

of reversing hypotension and/or substituting for impaired renal function; however, limited

experience with those procedures has not been associated with significant clinical benefit.

It is not known if ramipril or ramiprilat can be removed from the body by hemodialysis.

Animal Data: No teratogenic effects of ramipril were seen in studies of pregnant rats, rabbits,

and cynomolgus monkeys at doses up to 2500x, 6.25x and 1250x, respectively, the maximum

human dose. In rats, the highest dose (1000 mg/kg) caused reduced food intake in the dams, with

consequent reduced birth weights of the pups and weight development during the lactation

period. In rabbits, maternal effects were mortalities (≥100 mg/kg) and reduced body weight. In

monkeys, maternal effects were mortalities (≥50 mg/kg), vomiting, and reduced weight gain.

Nursing Women: The presence of concentrations of ACE inhibitor has been reported in human

milk. The use of ramipril is contraindicated during breastfeeding (see CONTRAINDICATIONS).

Pediatrics (< 18 years of age): The safety and effectiveness of ramipril in children have not been

established. Therefore, ramipril is not indicated in this patient population.

Geriatrics (>65 years of age): Although clinical experience has not identified differences in

response between the elderly (>65 years) and younger patients, greater sensitivity of some older

individuals cannot be ruled out. Evaluation of renal function at the beginning of treatment is

recommended (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and

Conditions, Geriatrics).


Monitoring and Laboratory Tests

Hematological Monitoring

It is recommended that the white blood cell count be monitored to permit detection of a possible

leukopenia. More frequent monitoring is advised in the initial phase of treatment and in patients:

- with impaired renal function,

- those with concomitant collagen disease (e.g. lupus erythematosus or scleroderma) or

- those treated with other drugs that can cause changes in the blood picture (see DRUG

INTERACTIONS, Drug-Drug Interactions, Allopurinol, Immunosuppressants,

Corticosteroids, Procainamide, Cytostatics and other substances that may change the

blood picture).

Renal Function Monitoring

Use of ramipril should include appropriate assessment of renal function, particularly in the initial

weeks of treatment.

Particularly careful monitoring is required in patients with:

- heart failure

- renovascular disease (atherosclerotic renal artery stenosis (AS-RAS) and fibromuscular

dysplasia (FMD)).

- impairment of renal function

- kidney transplant

- elderly patients

Electrolyte monitoring

It is recommended that serum potassium and serum sodium be monitored regularly. More

frequent monitoring of serum potassium is necessary in patients with impaired renal function.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

As ramipril is an antihypertensive; the most common adverse reactions are effects secondary to

its blood-pressure-lowering action.

In long-term safety studies in patients with hypertension the most commonly reported serious

adverse reactions were myocardial infarction (0.3%); edema (0.2%); hypotension (0.1%);

cerebrovascular accident (0.1%); and syncope (0.1%). Angioedema occurred in 0.1% patients

treated with ramipril and a diuretic.

The most frequent adverse events (AEs) occurring in these trials were: headache (15.1%);

dizziness (3.7%); asthenia (3.7%); chest pain (2.0%); nausea (1.8%); peripheral edema (1.8%);

somnolence (1.7%); impotence (1.5%); rash (1.4%); arthritis (1.1%); and dyspnea (1.1%).

Discontinuation of therapy due to clinical AEs was required in 0.8% of patients treated with

ramipril. Cough caused discontinuation of therapy approximately in 1% of patients in North

American controlled clinical trials.

Clinical Trial Adverse Drug Reactions


Because clinical trials are conducted under very specific conditions the adverse reaction

rates observed in the clinical trials may not reflect the rates observed in practice and

should not be compared to the rates in the clinical trials of another drug. Adverse drug

reaction information from clinical trials is useful for identifying drug-related adverse

events and for approximating rates.

Essential Hypertension

Ramipril was evaluated for safety in > 4000 hypertensive patients. Almost 500 elderly patients

participated in controlled trials. Long-term safety was assessed in almost 700 patients treated for

≥ 1 year. There was no increase in the incidence of adverse events in elderly patients given the

same daily dose. The overall frequency of AEs was not related to duration of therapy or total

daily dose.

Serious AEs occurring in North American placebo-controlled clinical trials with ramipril

monotherapy in hypertension (n= 972) were: myocardial infarction (0.3%); edema (0.2%);

hypotension (0.1%); cerebrovascular accident (0.1%); syncope (0.1%). Among all North

American ramipril patients (n= 1244), angioedema occurred in 0.1% patients treated with

ramipril and a diuretic.

The most frequent AEs occurring in these trials with ramipril monotherapy in hypertensive

patients that were treated for ≥ 1 year (n=651) were: headache (15.1%); dizziness (3.7%);

asthenia (3.7%); chest pain (2.0%); nausea (1.8%); peripheral edema (1.8%); somnolence (1.7%);

impotence (1.5%); rash (1.4%); arthritis (1.1%); dyspnea (1.1%). Discontinuation of therapy due

to clinical AEs was required in 5 patients (0.8%).

In placebo-controlled trials, an excess of upper respiratory infection and flu syndrome was seen

in the ramipril group. As these studies were carried out before the relationship of cough to ACE

inhibitors was recognized, some of these events may represent ramipril-induced cough. In a later

1-year study, increased cough was seen in almost 12% of ramipril patients, with about 4% of

these patients requiring discontinuation of treatment. Approximately 1% of patients treated with

ramipril monotherapy in North American controlled clinical trials (n=972) have required

discontinuation because of cough.

Less Common Adverse Drug Reactions (<1%)

Clinical AEs occurring in < 1% of patients treated with ramipril in controlled clinical trials are

listed below by body system:

Body as a Whole: angioedema.

Cardiovascular: angina pectoris, arrhythmia, chest pain, disturbed orthostatic regulation,

exacerbation of perfusion disturbances due to vascular stenosis, flushing, myocardial infarction,

palpitations, symptomatic-hypotension, syncope, tachycardia, vascular stenosis.

CNS: anxiety, amnesia, confusion, convulsions, depression, disorders of balance, hearing loss,

impaired hearing, insomnia, lightheadness, nervousness, neuralgia, neuropathy, paresthesia,


polyneuritis, restlessness, sleep disturbances, somnolence, tinnitus, tremor, vertigo, vision

disturbances, (including blurred vision).

Dermatologic: apparent hypersensitivity reactions (with manifestations of urticaria, pruritus, or

rash, with or without fever), photosensitivity, purpura.

In addition, the following cutaneous or mucosal reactions may occur: , erythroderma/exfoliative

dermatitis, maculopapular rash, maculopapular exanthema, onycholysis and psoriasiform

exanthema.

Gastrointestinal: abdominal discomfort, abdominal pain (sometimes with enzyme changes

suggesting pancreatitis), anorexia, constipation, diarrhea, digestive disturbances, decreased

appetite, dry mouth, dyspepsia, dysphagia, gastritis, gastroenteritis, glossitis, increased levels of

pancreatic enzymes, increased salivation, intestinal angioedema, nausea, pancreatitis (cases of

fatal outcome have been very exceptionally reported), taste disturbance, upper abdominal pain,

vomiting.

Hematologic: agranulocytosis, eosinophilia, leukopenia, thrombocytopenia (see WARNINGS

AND PRECAUTIONS, Hematologic, Neutropenia/agranulocytosis section).

Hepatobiliary: increased hepatic enzymes and/or conjugated bilirubin. Rarely, ACE inhibitors,

including ramipril, have been associated with a syndrome that starts with cholestatic jaundice and

progresses to fulminant hepatic necrosis and (sometimes) death.

Renal: impaired renal function, oliguria and acute renal failure. Increases in blood urea nitrogen

(BUN) and serum creatinine. Rarely, a deterioration of pre-existing proteinuria may develop

(though ACE inhibitors usually reduce proteinuria) or an increase in urinary output (in

connection with an improvement in cardiac performance).

Respiratory: bronchitis, bronchospasm (including aggravated asthma), increased cough, nasal

congestion, sinusitis.

Other: arthralgia, arthritis, conjunctivitis, depressed mood, dyspnea, edema, epistaxis,

impotence, increased sweating, loss of taste, malaise, muscle cramps, myalgia, reduced libido,

transient erectile impotence, weight gain.

A symptom complex has been reported which may include fever, vasculitis, myalgia,

arthralgia/arthritis, elevated erythrocyte sedimentation rate (ESR), eosinophilia and leukocytosis.

Rash, photosensitivity or other dermatologic manifestations may also occur.

Abnormal Hematologic and Clinical Chemistry Findings

The following abnormal hematologic and clinical chemistry findings have been reported:

decreases in red blood cell count, hemoglobin or hematocrit; elevations of liver enzymes, serum

bilirubin, uric acid, blood glucose; hyponatremia; increased creatinine; increases in blood urea

nitrogen (BUN); proteinuria and significant increases in serum potassium.

Post-Market Adverse Drug Reaction


Body as a whole: anaphylactoid reactions, angioedema (cases of fatal outcome have been

reported), fatigue.

Cardiovascular: cerebrovascular disorders (including ischaemic stroke and transient ischaemic

attack).

CNS: attention disturbances, burning sensation (mainly to skin of face or extremities), impaired

psychomotor skills (impaired reactions), precipitation or intensification of Raynaud’s

phenomenon, smell disturbances.

Dermatologic: erythema multiforms, exacerbation of psoriasis, lichenoid exanthema,

pemphigoid exanthema and enanthema, pemphigus, reversible alopecia, Stevens-Johnson

syndrome, toxic epidermal necrolysis.

Endocrine: Syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Gastrointestinal: aphtous stomatitis

Hematologic: pancytopenia, bone marrow depression and hemolytic anemia (see WARNINGS

AND PRECAUTIONS, Hematologic, Neutropenia/agranulocytosis section).

Hepatobiliary: acute hepatic failure, cholestatic or cytolytic jaundice, hepatitis (cases of fatal

outcome have been very exceptional), in isolated cases liver damage (including acute liver

failure) may occur.

Laboratory test findings: decrease in blood sodium.

Other: gynaecomastia, positive antinuclear antibodies (ANA).

DRUG INTERACTIONS

Drug-Drug Interactions

Table 1: Established or potential drug-drug interactions

Proper name Ref Effect Clinical comment

ENTRESTO® Sacubitril/valsartan

T The concomitant use of an ACE

inhibitor with ENTRESTO®

(sacubitril/ valsartan) is contraindicated, as the concomitant inhibition of neprilysin and ACE increases the risk of angioedema.

Concomitant use with ENTRESTO®

(sacubitril/valsartan) is contraindicated. Do

not initiate Sandoz Ramipril until 36 hours

after the last dose of sacubitril/valsartan. In

the case of a switch from Sandoz Ramipril

to sacubitril/valsartan, do not start

sacubitril/valsartan until 36 hours after the

last dose of Sandoz Ramipril (see

CONTRAINDICATIONS, and DOSAGE

AND ADMINISTRATION).



Acenocoumarol CT No significant change in blood

pressure, thrombotest time and

coagulation factors with

ramipril.

In a multi-dose double-blind, placebo-

controlled, pharmacodynamic interaction

study with 14 patients with mild hypertension

administered both ramipril and therapeutic

doses of acenocoumarol, blood pressure,

thrombotest time and coagulation factors were

not significantly changed.

Agents Causing Renin

Release

T Increased antihypertensive effect The antihypertensive effect of ramipril is

augmented by antihypertensive agents that

cause renin release (e.g. diuretics).

Agents Increasing Serum

Potassium

CT Since ramipril decreases

aldosterone production, elevation

of serum potassium may occur.

Potassium sparing diuretics such as

spironolactone, triamterene or amiloride,

potassium supplements, or other medicinal

products that may increase kalaemia should be

given only for documented hypokalemia and

with caution and frequent monitoring of

serum potassium, since they may lead to a

significant, sometimes severe, increase in

serum potassium. Salt substitutes which

contain potassium should also be used with

caution. (See also Non-Steroidal Anti-

Inflammatory Agents).

Alcohol C Increased vasodilatation Alcohol may potentiate the effect of ramipril.

Allopurinol,

immunosuppressants,

corticosteroids,

procainamide,

cytostatics and other

substances that may

change the blood picture

T Increased likelihood of hematological

reactions.

Antacids CT No effect In one open-label, randomized, cross-over

single dose study in 24 male subjects, it was

determined that the bioavailability of ramipril

and the pharmacokinetic profile of ramiprilat

were not affected by concomitant

administration of the antacid, magnesium and

aluminum hydroxides.

Antidiabetic Agents (e.g.

insulin and sulfonylurea

derivates)

CT ACE inhibitors may reduce insulin

resistance. In isolated cases, such

reduction may lead to

hypoglycemic reactions in patients

concomitantly treated with

antidiabetics

Particularly close blood glucose monitoring is

recommended in the initial phase of co-

administration.



Concomitant Diuretic

Therapy

CT Patients concomitantly taking ACE

inhibitors and diuretics, and

especially those in whom diuretic

therapy was recently instituted,

may occasionally experience an

excessive reduction of blood

pressure after initiation of therapy.

The possibility of hypotensive effects after the

first dose of ramipril can be minimized by

either discontinuing the diuretic or increasing

the salt intake prior to initiation of treatment

with ramipril. If it is not possible to

discontinue the diuretic, the starting dose of

ramipril should be reduced and the patient

should be closely observed for several hours

following the initial dose and until blood

pressure has stabilized (see WARNINGS

AND PRECAUTIONS and DOSAGE AND

ADMINISTRATION). Regular monitoring of

serum sodium is recommended in patients

undergoing concurrent diuretic therapy.

Desensitization therapy The likelihood and severity of

anaphylactic and anaphylactoid

reactions to insect venoma is

increased under ACE inhibition.

It is assumed that this effect may also occur in

connection with other allergens.

Digoxin CT In one open-label study in 12

subjects, administered multiple

doses of both ramipril and digoxin,

no changes were found in serum

levels of ramipril, ramiprilat, and

digoxin

DDP-IV inhibitors

(linagliptin, saxagliptin,

sitagliptin)

Patients taking concomitant DDP-

IV inhibitor therapy may be at

increased risk for angioedema.

Caution should be used when initiating

ramipril in patients already taking a DPP-IV

inhibitor or vice versa (see WARNINGS

AND PRECAUTIONS, General, Head and

Neck Angioedema).

Dual Blockade of the

Renin-Angiotensin-

System (RAS) with

ARBs, ACE inhibitors or

aliskiren-containing

drugs

CT, C Dual Blockade of the Renin-Angiotensin-

System with ACE inhibitors, including

Ramipril, ARBs or aliskiren-containing drugs

is contraindicated in patients with diabetes

and/or moderate to severe renal impairment

(see CONTRAINDICATIONS).

The use of ramipril in combination with an

ARB is contraindicated in patients with

diabetic nephropathy (see

CONTRAINDICATIONS).

Further, co-administration of ACE inhibitors,

including ramipril, with other agents blocking

the RAS, such as ARBs or aliskiren-

containing drugs, is generally not

recommended in other patients, since such

treatment has been associated with an

increased incidence of severe hypotension,

renal failure, and hyperkalemia. (See

CONTRAINDICATIONS and WARNINGS

AND PRECAUTIONS, Dual Blockade of the

Renin- Angiotensin-System (RAS))



Gold C Nitritoid reactions (symptoms

include facial flushing, nausea,

vomiting and symptomatic

hypotension) have been reported

rarely in patients on therapy with

injectable gold (sodium

aurothiomalate) and concomitant

ACE inhibitor therapy including

ramipril

Heparin T Rise in serum potassium

concentration is possible

Lithium CT Increased serum lithium levels and

symptoms of lithium toxicity have

been reported in patients receiving

ACE inhibitors during therapy with

lithium.

These drugs should be administered with

caution, and frequent monitoring of serum

lithium levels is recommended. If a diuretic is

also used, the risk of lithium toxicity may be

further increased.

mTOR inhibitors

e.g. sirolimus, everolimus,

temsirolimus

C An increased incidence of

angioedema was observed in

patients taking ACE inhibitors and

mTOR inhibitors (mammalian

target of rapamycin inhibitors).

Caution should be used when either initiating

ramipril in patients already taking mTOR

inhibitors or vice versa (see WARNINGS

AND PRECAUTIONS, Head and Neck

Angioedema).

Neutral endopeptidase

(NEP) inhibitors

T ACE inhibitors are known to cause

angioedema. This risk may be

elevated when used concomitantly

with a neutral endopeptidase

inhibitor

Caution should be used when initiating

ramipril in patients already taking a neutral

endopeptidase inhibitor or vice versa (see

WARNINGS AND PRECAUTIONS,

General, Head and Neck Angioedema).

Non-Steroidal Anti-

Inflammatory drugs

(NSAIDs) and

acetylsalicylic acid

CT The antihypertensive effects

of ACE inhibitors may be

reduced with concomitant

administration of NSAIDs

(e.g. indomethacin).

Concomitant treatment of

ACE inhibitors and NSAIDs

may lead to an increased risk

of worsening of renal

function and an increase in

serum potassium.

Avoid if possible. If not possible, close

monitoring of serum creatinine, potassium and

patient’s weight is recommended. Observe the

patient to ensure diuretic effects are obtained.

Monitor blood pressure and renal function.

Increase dose if necessary or discontinue

NSAID.

Other substances with

antihypertensive

potential (e.g. nitrates)

T Potentiation of the antihypertensive

effect is to be anticipated

Salt T Increased dietary salt

intake may attenuate the

antihypertensive effect

of ramipril.

Vasopressor

sympathomimetics

These may reduce the

antihypertensive effect of ramipril.

Particularly close blood pressure monitoring

is recommended.



Warfarin CT The coadministration of ramipril

with warfarin did not alter the

anticoagulant effects.

C = Case Study; CT = Clinical Trial; T = Theoretical

DOSAGE AND ADMINISTRATION

Recommended Dose and Dosage Adjustment

Essential Hypertension

Dosage of Sandoz Ramipril must be individualized. Initiation of therapy requires consideration of

recent antihypertensive drug treatment, the extent of blood pressure (BP) elevation and salt

restriction. The dosage of other antihypertensive agents being used with Sandoz Ramipril may

need to be adjusted.

Monotherapy The recommended initial dosage of Sandoz Ramipril in patients not on diuretics is 2.5 mg once

daily. Dosage should be adjusted according to BP response, generally, at intervals of ≥ 2 weeks.

The usual dose range is 2.5 - 10 mg once daily. The maximum daily dose is 20 mg.

In some patients treated once daily, the antihypertensive effect may diminish towards the end of

the dosing interval. This can be evaluated by measuring BP just prior to dosing to determine

whether satisfactory control is being maintained for 24 hours. If it is not, either twice daily

administration with the same total daily dose, or an increase in dose should be considered. If BP

is not controlled with Sandoz Ramipril alone, a diuretic may be added. After the addition of a

diuretic, it may be possible to reduce the dose of Sandoz Ramipril.

Concomitant Diuretic Therapy

Symptomatic hypotension occasionally may occur following the initial dose of Sandoz Ramipril

and is more likely in patients who are currently being treated with a diuretic. The diuretic should,

if possible, be discontinued for 2 - 3 days before beginning therapy with Sandoz Ramipril to

reduce the likelihood of hypotension (see WARNINGS AND PRECAUTIONS). If the diuretic

cannot be discontinued, an initial dose of 1.25 mg Sandoz Ramipril should be used with careful

medical supervision for several hours and until BP has stabilized. The dosage of Sandoz Ramipril

should subsequently be titrated (as described above) to the optimal response.

Use in renal impairment

For patients with a creatinine clearance < 40 mL/min/1.73m2 (serum creatinine > 2.5 mg/dL), the

recommended initial dose is 1.25 mg Sandoz Ramipril once daily. Dosage may be titrated upward

until BP is controlled or to a maximum total daily dose of 5 mg. In patients with severe renal

impairment (creatinine clearance < 10 mL/min/l.73m2), the maximum total daily dose is 2.5 mg

Sandoz Ramipril.

Use in hepatic impairment


The response to the treatment with ramipril may be either increased or reduced. Treatment in

these patients must therefore be initiated only under close medical supervision. The maximum

permitted daily dose in such cases is 2.5 mg.

OVERDOSAGE

Limited data are available regarding overdosage with ramipril in humans; only 2 cases of

overdosage have been reported.

In the case of an overdose with ramipril, the most likely clinical manifestation would be

symptoms attributable to severe hypotension, which should normally be treated by intravenous

volume expansion with normal saline.

Overdosage may cause excessive peripheral vasodilatation (with marked hypotension, shock),

bradycardia, electrolyte disturbances, and renal failure.

For management of a suspected drug overdose contact your regional Poison Control Centre

immediately.

Management

Primary detoxification by, for example, gastric lavage, administration of adsorbents, sodium

sulfate; (if possible during the first 30 minutes). In the event of hypotension administration of α1-

adrenergic agonists (e.g. norepinephrine, dopamine) or angiotensin II (angiotensinamide), which

is usually available only in scattered research laboratories, must be considered in addition to

volume and salt substitution.

No experience is available concerning the efficacy of forced diuresis, alteration in urine pH,

haemofiltration, or dialysis in speeding up the elimination of ramipril or ramiprilat. If dialysis or

haemofiltration is nevertheless considered, see also WARNINGS AND PRECAUTIONS,

Immune, Anaphylactoid reactions during membrane exposure section.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

Ramipril is an angiotensin converting enzyme (ACE) inhibitor.

Following oral administration, ramipril is rapidly hydrolyzed to ramiprilat, its principal active

metabolite.

ACE catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II.

Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. Inhibition of ACE

activity leads to decreased levels of angiotensin II thereby resulting in decreased vasoconstriction

and decreased aldosterone secretion. The latter decrease may result in a small increase in serum

potassium (see WARNINGS AND PRECAUTIONS, Endocrine and Metabolism, Hyperkalemia


and Potassium-Sparing Diuretics). Decreased levels of angiotensin II and the accompanying lack

of negative feedback on renal renin secretion result in increases in plasma renin activity.

ACE is identical to kininase II. Thus, ramipril may also block the degradation of the

vasodepressor peptide bradykinin, which may contribute to its therapeutic effect.

Pharmacodynamics

Administration of ramipril to patients with mild to moderate essential hypertension results in a

reduction of both supine and standing BP usually with little or no orthostatic change or change in

heart rate. Symptomatic postural hypotension is infrequent, although this may occur in patients

who are salt-and/or volume-depleted (see WARNINGS AND PRECAUTIONS).

In single dose studies, doses of 5-20 mg of ramipril lowered BP within 1-2 hours, with peak

reductions achieved 3-6 hours after dosing. At recommended doses given once daily,

antihypertensive effects have persisted over 24 hours.

The effectiveness of ramipril appears to be similar in the elderly (> 65 years of age) and younger

adult patients given the same daily doses.

In studies comparing the same daily dose of ramipril given as a single morning dose or as a twice

daily dose, BP reductions at the time of morning trough blood levels were greater with the

divided regimen.

While the mechanism through which ramipril lowers BP appears to result primarily from

suppression of the renin- angiotensin- aldosterone system (RAAS), ramipril has an

antihypertensive effect even in patients with low-renin hypertension.

The antihypertensive effect of ramipril and thiazide diuretics used concurrently is greater than

that seen with either agent used alone.

Abrupt withdrawal of ramipril has not resulted in rapid increase in BP.

Pharmacokinetics

Absorption: Following oral administration, ramipril is rapidly absorbed with peak plasma

concentrations occurring within 1 hour. The extent of absorption of ramipril is 50-60% and is not

significantly altered by the presence of food in the gastrointestinal tract, although the rate of

absorption is reduced.

Following a single administration of up to 5 mg of ramipril, plasma concentrations of ramipril

and ramiprilat increase in a manner that is greater than proportional to dose; after a single

administration of 5 mg to 20 mg of ramipril the plasma concentrations for both are dose-

proportional. The non-linear pharmacokinetics observed at the lower doses of ramipril can be

explained by the saturable binding of ramiprilat to ACE. At steady-state, the 24-hour AUC for

ramiprilat is dose-proportional over the recommended dose range. The absolute bioavailabilities

of ramipril and ramiprilat were 28% and 44% respectively when 5 mg of oral ramipril was

compared to 5 mg given intravenously.


Plasma concentrations of ramiprilat decline in a triphasic manner. The initial rapid decline, which

represents distribution of the drug, has a half life of 2-4 hours. Because of its potent binding to

ACE and slow dissociation from the enzyme, ramiprilat shows 2 elimination phases. The

apparent elimination phase has a half-life of 9-18 hours, and the terminal elimination phase has a

prolonged half-life of >50 hours. After multiple daily doses of ramipril 5-10 mg, the half-life of

ramiprilat concentrations was 13-17 hours, but was considerably prolonged at 2.5 mg (27-36

hours).

After once daily dosing, steady-state plasma concentrations of ramiprilat are reached by the 4th

dose. Steady-state concentrations of ramiprilat are higher than those seen after the 1st dose of

ramipril especially at low doses (2.5 mg).

Distribution: Following absorption, ramipril is rapidly hydrolyzed in the liver to its active

metabolite, ramiprilat. Peak plasma concentrations of ramiprilat are reached 2-4 hours after drug

intake. The serum protein binding of ramipril is about 73% and that of ramiprilat is 56%.

Metabolism: Ramipril is almost completely metabolized to the active metabolite ramiprilat, and

to the diketopiperazine ester, the diketopiperazine acid, and the glucuronides of ramipril and

ramiprilat, all of which are inactive.

Excretion: After oral administration of ramipril, about 60% of the parent drug and its

metabolites is excreted in the urine, and about 40% is found in the feces. Drug recovered in the

feces may represent both biliary excretion of metabolites and/or unabsorbed drug. Less than 2%

of the administered dose is recovered in urine as unchanged ramipril.

Special Populations and Conditions

Geriatrics: : A single dose pharmacokinetic study conducted in a limited number of elderly

patients indicated that peak ramiprilat levels and the AUC for ramiprilat are higher in older

patients (see WARNINGS AND PRECAUTIONS, Special Populations, Geriatrics).

Race: The antihypertensive effect of ACE inhibitors is generally lower in black patients than in

non-blacks.

Hepatic Insufficiency: In patients with impaired liver function, plasma ramipril levels increased

about 3-fold, although peak concentrations of ramiprilat in these patients were not different from

those seen in patients with normal hepatic function.

Renal Insufficiency: The urinary excretion of ramipril, ramiprilat, and their metabolites is

reduced in patients with impaired renal function. In patients with creatinine clearance

<40 mL/min/1.73 m2, increases in Cmax and AUC of ramipril and ramiprilat compared to normal

subjects were observed following multiple dosing with 5 mg ramipril (see DOSAGE AND

ADMINISTRATION, Recommended Dose and Dosage Adjustment, Use in renal impairment).

STORAGE AND STABILITY


Store Sandoz Ramipril in original container between 15 and 30oC, protect from light and

moisture and do not store beyond the date indicated on the container.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Availability of Dosage Forms

1.25 mg tablet - white, oblong, flat tablet, debossed “R” and “1.25” on one side only.

2.5 mg tablet - white oblong, flat tablet, debossed “R” and “2.5” on one side only.

5 mg tablet - white, oblong, flat tablet, debossed “R” and “5” on one side only.

10 mg tablet - white, oblong, flat tablet, debossed “R” and “10” on one side only.

Composition

Sandoz Ramipril tablets contain the following ingredients: Ramipril, sodium hydrogen carbonate,

hypromellose, microcrystalline cellulose, pregelatinized starch and sodium stearyl fumarate.

Packaging

Sandoz Ramipril is available in the following formats:

Al/Al blister packs of 30 tablets

HDPE bottles of 100 tablets


PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper Name: Ramipril

Chemical Name: 2-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(1S,3S,5S)-

2-azabicyclo-[3.3.0]octane-3-carboxylic acid

Empirical Formula: C23H32N2O5

Molecular Mass: 416.52 g/mol

Structural Formula:

Physicochemical Properties: A white to off-white crystalline powder with a melting

point of 105oC to 112oC. Slightly soluble in water, and

freely soluble in ethanol and methanol.


CLINICAL TRIALS

Comparative Bioavailability Study

Single dose crossover comparative bioavailability study of ramipril 10 mg tablets vs Altace®

10 mg capsules in 40 healthy male volunteers (18 to 50 years old) was conducted under fasted

conditions. Bioavailability data were measured and the results are summarized in the following

table.

Table 2 – Single Dose Crossover Comparative Bioavailability Study of Ramipril 10 mg Tablets vs Altace®

10 mg Capsules in 40 Healthy Male Volunteers- Fasted Conditions.

Ramipril

(1 x 10 mg)

From measured data

Uncorrected for potency

Geometric Mean

Arithmetic Mean (CV %)

Parameter

Test

Ramipril 10 mg

tablets

Reference

Altace®†

% Ratio of

Geometric Means 90 % Confidence Interval

AUCT

(ng·h/mL)

15.717

17.977 (50.6)

14.452

16.221 (50.6)

108.75 99.03- 119.44

AUCI

(ng·h/mL)

16.202

18.437 (49.8)

15.047

16.886 (50.0)

107.68 97.94- 118.39

CMAX

(ng/mL)

16.861

19.934 (54.2)

20.052

23.768 (75.6)

84.08 70.14- 100.79

TMAX*

(h)

0.67

(0.25-1.25)

0.50

(0.33-1.25)

T½**

(h)

1.15

(53.1)

1.67

(120.4)

† Altace® is manufactured by Sanofi-Aventis (former Hoechst Marion Roussel) and was purchased in

Canada. * Expressed as the median (range) only. ** Expressed as the arithmetic mean (CV %) only.


Single dose crossover comparative bioavailability study of ramipril 1.25 mg tablets vs Altace®

1.25 mg capsules in 42 healthy volunteers (8 females and 34 males), aged 18 to 50 years old, was

conducted under fasted conditions. Bioavailability data were measured and the results are

summarized in the following table.

Table 3 – Single Dose Crossover Comparative Bioavailability Study of Ramipril 1.25 mg Tablets vs Altace®

1.25 mg Capsules in 42 healthy volunteers (8 females and 34 males)- Fasted Conditions.

Ramipril

(1 x 1.25 mg)

From measured data

uncorrected for potency

Geometric Mean

Arithmetic Mean (CV %)

Parameter

Test

Ramipril

Sandoz Canada

Reference

Altace®

Hoechst marion

Roussel Canada

Inc., Canada

% Ratio of

Geometric Means 90% Confidence Interval

AUC0-t

(pg.h/mL)

2817.98

3033.38 (40.96)

2736.93

2968.62 (43.70)

102.96 96.85-109.46

AUC0-inf

(pg.h/mL)

2937.37

3167.03 (42.65)

2849.91

3104.28 (45.91)

103.07 96.87-109.67

Cmax

(pg/mL)

2589.54

2815.09 (41.59)

2751.25

3049.90 (50.42)

94.12 83.99-105.48

Tmax§

(h)

0.667 (0.166) 0.500 (0.167)

T½€

(h)

2.18 (37.57) 2.41 (58.31)

§ Expressed as the median (range) only

€ Expressed as the arithmetic mean (CV%) only


DETAILED PHARMACOLOGY

Table 4: Mechanism of Action

Study Species #/group Route Dose Results

Inhibition of

Angiotensin I- induced

pressor response after

oral ramipril

Rat

Dog

n=6

n=3

Oral

oral

0.1

0.3

1.0 mg/kg

A dose-dependent inhibition was

observed, lasting > 6 hours

Effect of pre-treatment

with ramipril on BP

changes induced by IV

Angiotensin I,

Angiotensin II, and

sympathomimetics

Rat

n=5

or

n=6

oral

1.0 mg/kg

Effects of Ang. I and indirect-

acting sympathomimetics are

inhibited, while the effects of Ang.

II and direct- acting

sympathomimetics are unaffected

by ramipril

Effect of ramipril on Na-

depleted (furosemide

treated) dogs

Dog

n=6

oral

10 mg/kg

Ramipril-induced increase in

plasma renin activity is enhanced

by furosemide; Ramipril has no

influence on heart rate

In vitro inhibition of

ACE by ramipril

Rabbit

lung

in vitro

IC50 =26±8 nmol/L

Effect of ramipril and

captopril on renal blood

flow, renal vasculature

resistance, and blood

pressure

Rat

n=5

i.a.

0.1 mg/kg

Ramipril caused a greater increase

in renal blood flow and decrease in

renal vasculature resistance than a

10-fold higher dose of captopril;

this without the decrease in

systemic BP observed with

captopril


Table 5: Effects on Blood Pressure

Hypertensive Model Species #/group Route Dose Duration Results

Spontaneously

hypertensive rats

Rat

n=5

oral

1 mg/kg

0.01, 0.1,

1, 10 mg/

kg/day

acute

5 weeks

Significant decreases in BP

(all doses); which persisted

for:

2 weeks (chronic)

72 hrs. (acute)

Kidney perinephretic

hypertension (no

increase in plasma

renin activity)

Dog

n=5

oral

10 mg/kg

1 mg/

kg/day

acute

5 days

Significant decrease of

systemic BP

2 kidney, 1 clip

hypertension

Rat

n=8

oral

1, 10 mg/kg acute

BP was normalized

Release of an occluded

renal pedicle

Rat

n=6

oral

0.1 mg/kg

acute

Hypertension was

completely prevented

Table 6: Pharmacokinetics and Bioavailability

Study Parameter

(after oral ramipril)

Results

Rat (2 mg/kg) Dog (2 mg/kg) Human (10 mg)

GI absorption of 14C-ramipril 56% 43% 56%

Maximal blood levels of

radioactivity

0.5 hrs 0.5-l hrs 0.3 hrs

Plasma t1/2 of radioactivity 0.6 hrs 1.0 and 3.8 hrs

(biphasic)

0.5 and 2.9 hrs

(biphasic)

Distribution of radioactivity

High concentration in

liver, kidney and

particularly lungs.

Total foetus :0.05%

Breast milk 0.25%

---

---

Serum protein binding

(concentration range of 0.01-10

mcg/mL)

ramipril:---

ramiprilat: 41%

ramipril: 72%

ramiprilat: 47%

ramipril: 73%

ramiprilat: 56%

Metabolism

metabolized to ramiprilat metabolized to ramiprilat and inactive

diketopiperazines

Excretion of radioactivity

urine: 26%

feces: 71%

t1/2 (both): 1.6- 4.8 and

23-42h

urine: 15%

t1/2: 9.3 h

feces: 79%

t1/2: 8h

urine: 56%

t1/2: 7.2 and 127h

feces: 40%

t1/2: 11 and 110 h


TOXICOLOGY

Acute Toxicity

Below are summarized species-specific LD50 values for both oral and intravenous (IV)

administrations of ramipril.

Table 7 - Acute Toxicity

Routes Species Sex LD50

Oral

Mouse

Male 10 933 mg/kg

Female 10 048 mg/kg

Rat Male >10 000 mg/kg

Female >10 000 mg/kg

Dog Male >1000 mg/kg

Intravenous Mouse Male 1194 mg/kg

Female 1158 mg/kg

Rat Male 688 mg/kg

Female 609 mg/kg

The symptoms observed in mice were decreased spontaneous activity, crouching, hypothermia,

dyspnea, and clonic convulsions; deaths occurred within 30 minutes after IV and 24 hours after

oral administration. In survivors, the symptoms disappeared by 1 - 5 days after administration;

necropsies revealed no abnormality in any of the surviving animals. In rats, reduced spontaneous

activity was noted (oral administration), while after IV administration similar signs occurred as in

mice; the sign of lethal toxicity was clonic convulsions (IV administration).

Table 8 - Chronic Toxicity

Species Duration

No. of

animals per

group

Route

Dose

(mg/kg/day)

Effects

Mouse 28 days

90 days

2M, 2F

3M, 3F

Oral 1000 Reduced erythrocytes, hemoglobin,

hematocrit, increased reticulocytes.

Hyperplasia of juxtaglomerular

apparatus.

Rat 30 days

10-15M

10-15F

Oral 2.5, 80, 2500

At all doses: decrease in body weight,

reduced liver weight, increased kidney

weight. At ≥80 mg/kg/d: Reduced

heart weight. At 2500 mg/kg/d:

Reduced erythrocytes, hematocrit and

bilirubin, increased BUN.


Table 8 - Chronic Toxicity (continued)

Species Duration

No. of

animals per

group

Route

Dose

(mg/kg/day)

Effects

Rat 3 months

10-15M

10-15F

Oral 2.5, 80, 500

At all doses: Reduced chloride

and glutaminic-oxalacetic

transaminase (GOT), increased

phosphorus and blood urea

nitrogen (BUN).

At 80 mg/kg/d: Reduced heart,

liver, prostate weights, increased

kidney weight. Atrophic segments

of renal tubules. Increased serum

creatinine. At 500 mg/kg/d:

Reduced body and heart weights,

increased kidney and adrenal

weights. Reduced erythrocytes,

hemoglobin, hematocrit, increased

bilirubin. Increased number of

atrophic renal tubular segments.

Moderate gastric mucosa necroses

Rat 3 months

10M, 10F

Oral 500, 1/3 Ringer

solution for

drinking

Increased number of tubular

atrophies.

Rat 6 months 10-20M

10-20F

Oral 0.1, 0.25, 3.2,

40, 500

At all doses: Serum bilirubin

increased, reduced heart weight.

At ≥ 40 mg/kg/d:

Increased kidney weight. Reduced

erythrocytes, hemoglobin,

hematocrit, increased BUN. Distal

tubular atrophies, fibromuscular

pad formations in gastric mucosa/

muscularis not proliferative in

nature.

Rat 6 months 20M, 20F Oral 3.2, 40, 500,

1/3 Ringer

solution for

drinking

All doses: Fibromuscular or

solitary pad formation in gastric

fundus mucosa/muscularis

Rat 18 months 20-25M

20-25F

Oral 0.25, 3.2, 40, 500

At ≥3.2 mg/kg/d:

Fibromuscular pads in gastric

fundus mucosa, focal atrophies in

renal cortex, partly with cysts.

At ≥40 mg/kg/d:

Anemia, increased BUN and

serum creatinine, urinary

epithelial cells. Reduced heart

weight and increased kidney and

adrenal weight.

Dog 30 days 2M, 2F Oral 3.2, 32 No pathological findings.


Table 8 - Chronic Toxicity (continued)

Species Duration

No. of

animals per

group

Route

Dose

(mg/kg/day)

Effects

Dog 3 months 3-4M

3-4F

Oral 3.2, 32, 320 At 320 mg/kg/d: Anemia,

increased BUN and serum

creatinine, impaired

erythropoiesis. Juxtaglomerular

hyperplasia.

Dog 6 months 6M, 6F Oral 3.2, 32, 320 At 32 mg/kg/d: Anemia,

juxtaglomerular hyperplasia. At

320 mg/kg/d: Reduced body

weight. Increased BUN and

serum creatinine. Distal tubular

atrophies with round cell

infiltrations. Anemia,

juxtaglomerular hyperplasia.

Dog 12 months 6M, 6F Oral 2.5, 25, 250 At all doses: Reduced body

weight.

At ≥25 mg/kg/d: Anemia and

leukopenia, impaired

erythropoiesis, increased

hemosiderin deposition in liver

and spleen, juxtaglomerular

hyperplasia.

At 250 mg/kg/d: Increased

BUN and serum creatinine.

Monkey 6 months 4-5M

4-5F

Oral 0.5, 16, 500

At ≥16 mg/kg/d: Increased

BUN, juxtaglomerular

hyperplasia. Reduced body

weight.

At 500 mg/kg/d: Diarrhea,

anemia, increased serum

creatinine, some urinary casts,

leukocytes and epithelial cells.

Monkey 6 months 5M

5F

Oral 2, 8

No pathological findings.


Table 9 – Reproduction and Teratology:

Species No. of

animals

per group

Dose

(mg/kg/day)

Duration of

dosing

Results

Rat

(Wistar)

32M, 32F 5, 50, 500 M 60 days

before mating

F 14 days

before mating

to end of

lactation

At ≥ 50 mg/kg/d: Parents renal pelvis enlargement,

offspring light brown discolouration of kidney

tissue and dilatation of renal pelvis.

At 500 mg/kg/d: Parents yellow white colouring

and induration of renal marrow. Fertility normal.

Rat

(Wistar)

20F

10, 100,

1000

Days 7-17 of

gestation

At 1000 mg/kg/d: Reduced food consumption of

mothers, reduced body weight gains of young. One

young circular non-ossified area in supraoccipital

bone, 1 young distortion of right scapula. No

teratogenic effects.

Rat

(Wistar)

20-30F 0.32, 1.25,

5, 10, 100,

1000

Day 17 of

gestation to

day 21 of

lactation

At ≥100 mg/kg/d: Decreased gestation body

weight of young, enlarged to day 21 renal pelvis

up to hydronephrosis with light brown colouring

of renal cortex and marrow.

Rat

(Sprague-

Dawley)

20F

100

Day 17 of

gestation to

day 21 of

lactation

Young: Enlarged renal pelvis and light brown

colouration of kidney tissue.

Rabbit

(Himalayan)

15F

0.4, 1, 2.5

Day 6 to day

18 of gestation

At 0.4 mg/kg/d: 1 abortion, 1 foetus with

diaphragm hernia. At 1 mg/kg/d: 1 abortion, 1

premature delivery, 2 animals died, no animals

gained weight. One dead foetus with possible

hydrocephalus.

At 2.5 mg/kg/d: 2 animals died, no animals gained

weight, 1 foetus with diaphragm hernia, 1 with

first cervical aplasia and aplasia of 1 thorax

vertebra and 1 rib pair.

Monkey

(Cynomolgus)

4-13F

5, 50, 500

Days 20- 25 of

gestation

At all doses: No sign of teratogenesis.

At 5 mg/kg/d: 2 abortions, 7 diarrhea, 2 vomiting,

10 weight loss.

At 50 mg/kg/d: 1 animal died, 3 abortions, 7

diarrhea, 2 vomiting, 10 weight loss.

At 500 mg/kg/d: 3 animals died, 1 abortion, 4

weight loss, 4 vomiting, 4 diarrhea.

Mutagenicity:

Ramipril was not mutagenic in the Ames microbial mutagen test, the HGPRT test in V79 cells,

the micronucleus test in mice and the UDS test in human A549 cells.

Carcinogenicity:

There was no evidence of a carcinogenic effect when ramipril was administered for 104 weeks to

NMRI mice at doses ≤1000 mg/kg/day and to Wistar rats at doses ≤500 mg/kg/day.


REFERENCES

1. Burris JF. The Effect of Ramipril on Ambulatory Blood Pressure: A Multicenter Trial. J

of Cardiovascular Pharmacology 1991, 18(Suppl 2): S131-S133.

2. Carré A, Vasmant D, Elmalem J, et al. Tolerability of Ramipril in a Multicenter Study of

Mild-to-Moderate Hypertension in General Practice. J of Cardiovascular Pharmacology

1991, 18(Suppl 2): S141-S143.

3. Heidbreder K, Froer K-L, Bauer B et al. Efficacy and Safety of Ramipril in Combination

with Hydrochlorothiazide: Results of a Long-Term Study. J of Cardiovascular

Pharmacology 1991, 18(Suppl 2): S169- S173.

4. Hosie J and Meredith P. The Pharmacokinetics of Ramipril in a Group of Ten Elderly

Patients with Essential Hypertension. J of Cardiovascular Pharmacology 1991, 18 (Suppl

2): S125- S127.

5. Lenox-Smith AJ, Street RB and Kendall FD. Comparison of Ramipril Against Atenolol in

Controlling Mild-to-Moderate Hypertension. J of Cardiovascular Pharmacology 1991,

18(Suppl.2): S150- S152.

6. Manhem PJO, Ball SG, Morton JJ, Murray GD, Leckie BJ, Fraser R, Robertson JIS. A

dose-response study of Hoe 498, a new non-sulphydryl converting enzyme inhibitor, on

blood pressure, pulse rate and the renin- angiotensin- aldosterone system in normal man.

Br J Clin Pharmacol 1985, 20: 27-35.

7. McCarron D and The Ramipril Multicenter Study Group. 24-Hour Blood Pressure

Profiles in Hypertensive Patients Administered Ramipril or Placebo Once Daily:

Magnitude and Duration of Antihypertensive Effects. Clin Cardiol 1991, 14: 737-742.

8. Reinich W, Hoffmann H, Hoffmann W. Treatment of hypertension with the new ACE-

inhibitor Ramipril. (Translation) Therapiewoche Österreich 1992, 7: 112-119.

9. Rosenthal J, Buehler G, Koenig W, et al. Effect of Angiotensin-Converting Enzyme

Inhibition on Human Tissue Renin. J of Cardiovascular Pharmacology 1991, 18 (Suppl

2): S122- S124.

10. Saalbach R, Wochnik G, Mauersberger H, et al. Antihypertensive Efficacy, Tolerance,

and Safety of Ramipril in Young vs Old Patients: A Retrospective Study. J of

Cardiovascular Pharmacology 1991, 18(Suppl 2): S134- S136.

11. Schnaper HW. Dose-Response Relationship of Ramipril in Patients with Mild-to-

Moderate Hypertension. J of Cardiovascular Pharmacology 1991, 18(Suppl. 2): S128-

S130.


12. Schreiner M, Berendes B, Verho M, et al. Antihypertensive Efficacy, Tolerance, and

Safety of Long-Term Treatment with Ramipril in Patients with Mild-to-Moderate

Essential Hypertension. J of Cardiovascular Pharmacology 1991, 18 (Suppl 2): S137-

S140.

13. Vasmant D, Lendresse P, Lemarie J-C, et al. Comparison of Response Rates to the

Angiotensin-Converting Enzyme Inhibitor Ramipril in Mild-to-Moderate Hypertension in

a Double-Blind, Parallel-Group Study and an Open Single-Blind Study. J of

Cardiovascular Pharmacology 1991, 18(Suppl 2): S144- S146.

14. Vierhapper H, Witte U, Waldhausl W. Unchanged pressor effect of norepinephrine in

normal man following the oral administration of two angiotensin converting enzyme

inhibitors, captopril and Hoe 498. J Hypertens 1986, 4: 9-11.

15. Valeant Canada LP, Altace (ramipril capsule), Product Monograph, control number:

212643, Date of Revision: April 12, 2018.

IMPORTANT: PLEASE READ


PART III: CONSUMER INFORMATION

PrSANDOZ RAMIPRIL

( ramipril tablets )

Read this carefully before you start taking Sandoz Ramipril

and each time you get a refill. This leaflet is a summary and

will not tell you everything about Sandoz Ramipril. Talk to

your doctor, nurse, or pharmacist about your medical

condition and treatment and ask if there is any new

information about Sandoz Ramipril.

ABOUT THIS MEDICATION

What the medication is used for:

High Blood Pressure (Hypertension)

Sandoz Ramipril lowers high blood pressure. It can be used alone

or together with a diuretic (“water pill”).

Managing your lifestyle:

Keeping your blood pressure controlled

It takes more than just medication to reduce blood pressure.

Discuss the risk factors, and how they apply to your lifestyle, with

your doctor. You may have to modify some of your daily habits to

keep your blood pressure down.

Exercise regularly. It will help to keep your weight down, make

you feel more energetic and is a good way to deal with stress. If

you are not exercising regularly, be sure to discuss a fitness plan

with your doctor.

Remember, hypertension is a long-term disease without

symptoms. Just because you feel fine does not mean you can stop

taking your medication. If you stop, serious complications of the

disease may occur. Therefore, you should continue to take Sandoz

Ramipril regularly, as prescribed by your doctor.

The “lifestyle” part of your treatment is as important as your

medication. By working as a team with your doctor, you can help

reduce the risk of complications to maintain the style of life you

are accustomed to.

• Alcohol: Avoid alcoholic beverages until you have discussed

their use with your doctor. Alcohol consumption may alter

your blood pressure and/or increase the possibility of

dizziness or fainting.

• Diet: Generally, avoid fatty foods and food that is high in salt

or cholesterol.

• Smoking: Avoid it completely.

What it does:

Sandoz Ramipril is an angiotensin converting enzyme (ACE)

inhibitor. You can recognize ACE inhibitors because their

medicinal ingredient ends in ‘-PRIL’.

This medicine does not cure your disease. It helps to control it.

Therefore, it is important to continue taking Sandoz Ramipril

regularly even if you feel fine.

When it should not be used:

Do not take Sandoz Ramipril if you:

Are allergic to ramipril or to any non-medicinal ingredient in

the formulation.

Have experienced an allergic reaction (angioedema) with

swelling of the hands, feet, or ankles, face, lips, tongue,

throat, or sudden difficulty breathing or swallowing, to any

ACE inhibitor or without a known cause. Be sure to tell your

doctor, nurse, or pharmacist that this has happened to you.

Have been diagnosed with hereditary angioedema: an

increased risk of getting an allergic reaction that is passed

down through families. This can be triggered by different

factors, such as surgery, flu, or dental procedures.

Are pregnant or intend to become pregnant. Taking Sandoz

Ramipril during pregnancy can cause injury and even death

to your baby.

Are breastfeeding. Ramipril passes into breast milk.

Are taking ENTRESTO ® (sacubitril/valsartan), due to the

increased risk of serious allergic reaction which causes

swelling of the face or throat (angioedema) when taken with

Ramipril. You must wait at least 36 hours after your last

dose of sacubitril/valsartan before taking Sandoz Ramipril.

Have narrowing of the arteries to one or both kidneys (renal

artery stenosis).

Have hypotension (low blood pressure).

Are on dialysis or LDL apheresis (a treatment to remove LDL

cholesterol from the blood).

are already taking a blood pressure-lowering medicine that

containing aliskiren (such as Rasilez) and you have one of

the following conditions:

diabetes

kidney disease

high potassium levels

heart failure combined with low blood pressure

Are taking an angiotensin receptor blocker (ARB), another

medicine to treat your high blood pressure, or another ACE

inhibitor and have one of the following conditions:

diabetes with end organ damage

kidney disease

high potassium levels

heart failure combined with low blood pressure

You can recognize an ARB because its medicinal ingredient ends

in “-SARTAN”.

What the medicinal ingredient is:

Ramipril

What the important nonmedicinal ingredients are:

Hypromellose, microcrystalline cellulose, pregelatinized starch,

sodium hydrogen carbonate and sodium stearyl fumarate.

What dosage forms it comes in: Tablets 1.25 mg, 2.5 mg, 5 mg and 10 mg.



WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions - Pregnancy

Sandoz Ramipril should not be used during pregnancy. If

you discover that you are pregnant while taking ramipril,

stop the medications and please contact your doctor, nurse,

or pharmacist as soon as possible.

BEFORE you use Sandoz Ramipril talk to your doctor, nurse, or

pharmacist if you:

Are allergic to any drug used to lower blood pressure.

Have recently received or are planning to get allergy shots

for bee or wasp stings.

Have narrowing of an artery or a heart valve.

Have had a heart attack or stroke.

Have heart failure.

Have diabetes, liver or kidney disease.

Are on dialysis or LDL apheresis (a treatment to remove

LDL cholesterol from the blood).

Are dehydrated or suffer from excessive vomiting, diarrhea,

or sweating.

Are taking a salt substitute that contains potassium,

potassium supplements, a potassium-sparing diuretic (a

specific kind of “water pill”), or other medicinal products

that may increase potassium. Use of Sandoz Ramipril with

these medicines is not recommended.

Are on a low-salt diet.

Are receiving gold (sodium aurothiomalate) injections.

Are less than 18 years old.

Are taking a medicine that contains aliskiren, such as

Rasilez, used to lower high blood pressure. The combination

with Sandoz Ramipril is not recommended.

Are taking an angiotensin receptor blocker (ARB). You

can recognize an ARB because its medicinal ingredient

ends in “-SARTAN”. The combination with Sandoz

Ramipril is not recommended.

Are taking drugs such as:

o Temsirolimus and everolimus (used to treat cancer),

o Sirolimus (used to prevent organ rejection after a

transplant),

o Sitagliptin or other gliptins (used to treat Type II

diabetes),

o A neutral endopeptidase inhibitor.

Taking ACE inhibitors, such as Sandoz Ramipril, with these types

of drugs may increase your chances of having an allergic reaction

(angioedema). You may become sensitive to the sun while taking

Sandoz Ramipril. Exposure to sunlight should be minimized until

you know how you respond.

If you are going to have surgery and will be given an anesthetic,

be sure to tell your doctor or dentist that you are taking Sandoz

Ramipril.

Driving and using machines: Before you perform tasks which

may require special attention, wait until you know how you

respond to Sandoz Ramipril. Dizziness, lightheadedness, or

fainting can especially occur after the first dose and when the dose

is increased.

Raynaud's phenomenon is a condition resulting from poor

circulation in the extremities (i.e., fingers and toes). It may begin

or get worse.

INTERACTIONS WITH THIS MEDICATION

As with most medicines, interactions with other drugs are

possible. Tell your doctor, nurse, or pharmacist about all the

medicines you take, including drugs prescribed by other doctors,

vitamins, minerals, natural supplements, or alternative medicines.

The following may interact with Sandoz Ramipril:

Agents increasing serum potassium, such as a salt substitute

that contains potassium, potassium supplements, or a

potassium-sparing diuretic (a specific kind of “water pill”), or

other medicinal products that may increase potassium. Use of

Sandoz Ramipril with these medicines is not recommended.

Alcohol

Allopurinol used to treat gout.

Antidiabetic drugs, including insulin and oral medicines,

such as gliptins (e.g. sitagliptin)

Lithium used to treat bipolar disease.

Gold for the treatment of rheumatoid arthritis.

Nonsteroidal anti-inflammatory drugs (NSAIDs), used to

reduce pain and swelling. Examples include ibuprofen,

naproxen, and celecoxib.

Blood pressure lowering drugs, including diuretics (“water

pills”), aliskiren-containing products (e.g. Rasilez), or

angiotensin receptor blockers (ARBs).

Nitrates used to treat angina (chest pain)

Acetylsalicylic acid (aspirin)

Heparin used to prevent and treat blood clots

Immunosuppressants used to lower the body’s ability to

reject a transplanted organ

Corticosteroids used to treat joint pain and swelling or for

other conditions.

Procainamide used to treat irregular heartbeat

Cytostatic medicines used to treat certain types of cancer

mTOR inhibitors used to lower the body’s ability to reject a

transplant (e.g. sirolimus) or to treat certain types of cancer

(e.g. tersirolimus, everolimus)

Neutral endopeptidase (NEP) inhibitors.

PROPER USE OF THIS MEDICATION

Take Sandoz Ramipril exactly as prescribed. It is recommended to

take your dose at about the same time every day.

Usual adult dose:

High Blood Pressure: The recommended initial dosage of

Sandoz Ramipril is 2.5 mg once daily. Your doctor will determine

the appropriate dosage.



For patients taking diuretics (“water pills”) or with impaired

kidney function: The recommended initial dosage of ramipril is

1.25 mg daily.

Overdose:

If you think you have taken too much Sandoz Ramipril contact

your doctor, nurse, pharmacist, hospital emergency department

or regional Poison control Centre immediately, even if there are

no symptoms.

Missed Dose:

If you have forgotten to take your dose during the day, carry on

with the next one at the usual time. Do not double dose.

SIDE EFFECTS AND WHAT TO DO ABOUT THEM

Side effects may include:

dizziness difficulty in maintaining your balance while

standing

drowsiness, fatigue, weakness

cough, nasal or sinus congestion, swollen lymph nodes,

bronchitis, aggravated asthma

rash, itching, flushing, inflammation of the eye (pink eye),

skin inflammation or red skin, burning sensation,

inflammation of the mouth or tongue

headache

abdominal pain

sad mood, difficulty with sleep, restlessness, attention

disturbances

loss of hair taste modifications or loss of taste, vision or

hearing modifications impotence/reduced libido, breast

enlargement in males

If any of these affects you severely, tell your doctor, nurse or

pharmacist.

Sandoz Ramipril can cause abnormal blood test results. Your

doctor will decide when to perform blood tests and will interpret

the results.

SERIOUS SIDE EFFECTS, HOW OFTEN THEY HAPPEN

AND WHAT TO DO ABOUT THEM

Symptom/Effect Talk with your

doctor, nurse, or

pharmacist

Stop taking

drug and seek

immediate

medical help Only if

severe

In all

cases

Common Low Blood Pressure:

dizziness, fainting,

lightheadedness

May occur when you go

from lying or sitting to

standing up.

√

SERIOUS SIDE EFFECTS, HOW OFTEN THEY HAPPEN

AND WHAT TO DO ABOUT THEM

Symptom/Effect Talk with your

doctor, nurse, or

pharmacist

Stop taking

drug and seek

immediate

medical help Only if

severe

In all

cases

Increased levels of

potassium in the blood:

irregular heartbeat, muscle

weakness and generally

feeling unwell

√

Uncommon Allergic Reaction:

rash, hives, swelling of the

face, arms and legs, lips,

tongue or throat, difficulty

swallowing or breathing

√

Kidney Disorder:

change in frequency of

urination, nausea,

vomiting, swelling of

extremities, fatigue

√

Liver Disorder:

yellowing of the skin or

eyes, dark urine,

abdominal pain, nausea,

vomiting, loss of appetite

√

Electrolyte Imbalance:

weakness, drowsiness,

muscle pain or cramps,

irregular heartbeat

√

Rare Decreased Platelets:

bruising, bleeding, fatigue

and weakness

√

Decreased White Blood

Cells:

infections, fatigue, fever,

aches, pains, and flu-like

symptoms

√

Heart Attack:

chest pain and/or

discomfort, pain in the jaw,

shoulders, arm and/or

back, shortness of breath,

sweating, lightheadedness,

nausea

√

Cerebrovascular

accident/ Stroke:

weakness, trouble

speaking, trouble seeing,

headache, dizziness

√

Intestinal Angioedema:

abdominal pain (with or

without nausea or

vomiting)

√



This is not a complete list of side effects. For any unexpected

effects while taking Sandoz Ramipril, contact your doctor, nurse

or pharmacist.

HOW TO STORE IT

Store in original container between 15 and 30°C, protect from

light and moisture and do the date indicated on the container.

Keep out of reach of children.

Reporting Side Effects

We encourage you to report serious or unexpected side effects to

Health Canada. The information is used to check for new safety

concerns about health products. As a consumer, your report

contributes to the safe use of health products for everyone.

3 ways to report:

Online at MedEffect; (https://www.canada.ca/en/health-

canada/services/drugs-health-products/medeffect-canada.html)

By calling 1-866-234-2345 (toll-free);

By completing a Consumer Side Effect Reporting Form

and sending it by:

- Fax to 1-866-678-6789 (toll-free), or

- Mail to: Canada Vigilance Program

Health Canada, Postal Locator 1908C

Ottawa, ON

K1A 0K9

Postage paid labels and the Consumer Side Effect

Reporting Form are available at MedEffect.

(https://www.canada.ca/en/health-

canada/services/drugs-health-products/medeffect-

canada.html)

NOTE: Should you require information related to the

management of side effects, contact your health professional. The

Canada Vigilance Program does not provide medical advice.

MORE INFORMATION

This document, plus the full Product Monograph prepared for

health professionals, can be obtained by contacting the sponsor,

Sandoz Canada Inc., at: 1-800-361-3062

or by written request at:

145, Jules-Léger

Boucherville, (QC), Canada

J4B 7K8

or by e-mail at :

[email protected]

This leaflet was prepared by Sandoz Canada Inc.

Last revised: June 22, 2018

ENTRESTO® is a trade-mark of Novartis AG, Switzerland.

http://hc-sc.gc.ca/dhp-mps/medeff/index-eng.php

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Documents

PRODUCT MONOGRAPH - Sandoz Canada · Sandoz Ramipril Page 1 of 37 PRODUCT MONOGRAPH Pr SANDOZ RAMIPRIL Ramipril Tablets 1.25 mg, 2.5 mg, 5.0 mg and 10.0 mg Manufacturer's Standard